CN104736145A - Gastroretentive drug formulation and delivery systems and their method of preparation using functionalized calcium carbonate - Google Patents
Gastroretentive drug formulation and delivery systems and their method of preparation using functionalized calcium carbonate Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
An instantly floating gastroretentive drug formulation comprising at least one functionalized natural and/or synthetic calcium carbonate-comprising mineral and at least one pharmaceutically active ingredient and at least one formulating aid wherein said functionalized natural or synthetic calcium carbonate is a reaction product of natural or synthetic calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is formed in situ by the acid treatment and/or is supplied from an external source.
Description
Technical field
The present invention relates to the gastric retention medicine preparaton and delivery system and preparation method thereof that use functionalized calcium carbonate.Gastric retention medicine delivery system is at once floating and can be the form of tablet, micro tablet, granule, capsule or pill.Gastric retention medicine delivery system is intended to keep an elongated segment under one's belt and the predictable time, delivering active ingredients or nonactive presoma.At once swim in and hereinafter refer to that time delay is zero before the floating generation of reality.
Background technology
Compared to conventional dosage forms, gastric retention drug delivery system (GRDDS) is through designing to keep an elongated segment under one's belt and the predictable time cycle.Therefore, medical substance gastric residence extend and biological usability be improved.GRDDS is useful for multi-medicament, if its action site is the medical substance and under one's belt or show the medicine of narrow absorption window in upper part of small intestine of local under one's belt.In addition, the medicine of degrading in intestinal or colonic environment and under alkaline ph values the medical substance of poorly soluble be the material standed for benefiting from GRDDS.
Propose to realize gastric retention and avoided the various mechanism of uncertain dosage form gastric emptying.These methods comprise: the common throwing of medicine or drug excipient (affect gastric motility pattern and postpone gastric emptying process thus), magnetic systems, mucosa adhesion system, increase system, the density control system floated on gastric content or deposition owing to the size expanded or launch, and combined system.
The people such as Pawar (Gastroretentive dosage forms:A review with specialemphasis on floating drug delivery systems.Drug Delivery.2011 February; 18 (2): 97-110.) floating drug delivery system (FDDS) is considered as about the preparaton of GRDDS exploitation and a kind of easy of technical elements and the method for logic.FDDS is that density is less than gastric juice density (about 1.004g/cm
3) low density systems.Therefore, dosage form to float on gastric content and retains under one's belt while release medicine.
Since Davis describes the idea (US 3,418,999) of floating dosage form in nineteen sixty-eight, the Different Strategies of preparation FDDS has been invented by many research teams.By introducing low density material, realizing flotation by expanding or producing by gas and retain.There is provided at once floating because density is less than overall excipient to delivery apparatus, be therefore very favorable concerning its use for preparaton exploitation.
US 3,976,764 discloses one floating tablet at once, and it has and scribbles some internally coated hollow balls based on gelatin, and wherein therapeutic activity composition is comprised in one of undercoating.
DE 35 27 852 A1 discloses a kind of specific density lower than the pharmaceutical formulation of 1, in water, wherein forms the material of gel with active constituents of medicine and at room temperature for the fats/oils of solid mixes.This gel formation material is cellulose derivative, glucan derivative or starch derivatives.
EP 0 338 861 A2 mentions a kind of antacid compositions with the gastric retention time of prolongation.
The antacid of such as brucite (Hydrotalcite) or amalgam (Amalgate) forms the solid core of being surrounded mutually by outer solid, this outer solid contains lyophobic dust mutually, such as glycerol and Palmic acid or stearic ester, hydroxylating polyolefin and nonionic emulsifier.
EP 0 717 988 A1 mentions a kind of bulging die product, and it is have netted cross section and the apparent density expansion structure that is less than 1, and this structure is mainly acidproof polymer compound and in addition containing at least auxiliary blowing agent and medical substance.Because the network structure in its cross section, so the bulging die product of this invention has a large amount of continuous or discrete fine endoporus.Described acidproof polymer compound is selected from such as hydroxypropyl emthylcellulose acetic acid succinate or phthalic acid ester.
US 4,451,260 mentions a kind of multiple structure comprising active constituents of medicine, and wherein air is retained in this multiple structure, promotes floating thus.
US 4,814,179 mentions a kind of float slow release therapeutic combination.Uncompressed slow releasing tablet comprises hydrocolloid gelling agents, treats acceptable inert oil, therapeutic agent through selecting and water.
The existence that proportion is less than the pharmaceutical inert fat material of 1 reduces hydrophilic and the buoyancy of the dosage form improved.
Most preferably floating tablet has different conflicting characteristics.On the one hand, there is high porosity to swim on gastric content, there is enough hardness to tolerate the damage of gastric peristalsis on the other hand.In addition, have the high porosity of actively impact also to have shortcoming: on floating especially when hole interconnects, when hole is exposed to gastric juice, water can be filled in access aperture, and even diffuses to the more depths in hole simultaneously.Therefore, intrinsic density will increase and thus reduce the floating capacity of tablet, and cause tablet to sink at subsequent stage thus, and bear since it is known mechanism (as wriggled) and the risk comparatively early removed in stomach.Prior art solves this problem by acid being comprised under carbonate existence in its preparaton.Upon contact with water, acid discharges CO
2, and by this foaming mechanism, tablet keeps floating.But its shortcoming is that this kind of tablet dissolved is faster, and counteracts long residence time under one's belt thus.
Summary of the invention
Thus the present invention provides a kind of at once floating preparaton with gastric retention performance overcoming the shortcoming existed at present.
The present inventor finds surprisingly, and the particle from paper industry can serve as the novel drugs excipient with highly porous network, and this highly porous network has the laminar surface structure of to be kept a firm hand on by particle together.Due to its special performance, therefore functionalized calcium carbonate (FCC) is hopeful for the preparation of FDDS.Thus be likely mixed with granule, pill, capsule or be pressed into relative density and be less than one and (be also namely less than 1.000g/cm
3) tablet or micro tablet.
The functionalized natural and/or synthetic calcium carbonate (FCC) comprised in gastric retention drug delivery system can by containing the mineral of natural ground calcium carbonate or preparing by synthetic calcium carbonate (sometimes also referred to as winnofil) or by the natural admixture with synthetic calcium carbonate.The present invention also comprises the method for this gastric retention preparaton of preparation and delivery system.
At once floating gastric retention delivery system can be selected from tablet, micro tablet, granule or pill.Another kind of dosage form is capsule.As represented by its term, swim in immediately on the surface of gastric juice after at once swimming in absorption.Therefore do not need to start floating mechanism.At once the density of floating solubility gastric retention delivery system (is about 1.004g/cm lower than gastric juice density
3).Thus, the flotation property in initial flotation property and gastric juice during gastric retention preparaton release medicine is maintained, until gastric retention preparaton dissolves completely.These flotation properties realize by the mineral comprising functionalized calcium carbonate being mixed with the at once floating gastric retention preparaton that comprises at least one active constituents of medicine or nonactive presoma, formulation aid and other optional additive (as film forming matter, flavoring agent, lubricant, effervescent composition or coloring agent).Suitable composition to be described in prior art and to be contained in and generally believes in the FDA food additive inventory of safety (GRAS), but is not limited thereto.
The invention further relates to a kind of method or the technique that manufacture this kind of floating and gastric retention preparaton at once and its dosage form.
Mineral containing functionalized calcium carbonate carry out dry type or wet granulation together with granulating assistant by known method together with at least one active component or nonactive presoma.Granule can direct quantitative administration when being packaged in medicated bag or bar-shaped bag (stick packs), or (such as density is lower than 1.000g/cm lower than the pill of gastric juice density to be optionally pressed into tablet, micro tablet (also namely diameter is less than the tablet of 3mm) or density
3).Another kind of dosage form can also be capsule form.
The present invention relates to a kind of floating gastric retention drug delivery system at once and use functionalized calcium carbonate to manufacture its method.At once floating gastric retention drug delivery system of the present invention comprises the preparaton of floating composition at once.
Described floating gastric retention preparaton at once comprises at least one containing the mineral of functionalized natural and/or synthetic calcium carbonate and at least one active constituents of medicine and at least one formulation aid, wherein said functionalized natural or synthetic calcium carbonate is natural or synthetic calcium carbonate and carbon dioxide and one or more acid product, and wherein this carbon dioxide is formed by acid treatment original position and/or supplied by external source.
Containing the appropriate amount of the mineral of functionalized natural or synthetic calcium carbonate based on total composition meter in 30wt% to 95wt% scope.
Also can use lower amount, but when making preparaton, buoyancy may be influenced, also can sharply reduce even if its mode is the words making floating capacity not lose completely.
Natural whiting source for the preparation of functionalized calcium carbonate (FCC) is selected from marble, calcite, Chalk, limestone and dolomite and/or its mixture.
In a particular embodiment, synthetic calcium carbonate for the preparation of this functionalized calcium carbonate is the winnofil (PCC) comprising aragonitic, vaterite-type or calcite type mineral crystal form, especially prismatic, rhombohedron shape or scalenohedron shape PCC or its mixture.
The present technique that will further describe for the preparation of functionalized natural and/or synthetic calcium carbonate (FCC).
In a preferred embodiment, natural or synthetic calcium carbonate ground before by one or more acid and carbon dioxide treatment.Grinding steps can carry out with any traditional lapping device (as grinder) coming well known by persons skilled in the art.
In a kind of selection process, suspend in water through segmentation (as grinding) or the natural or synthetic calcium carbonate that do not segment.Preferably, slurry has based on slurry weight meter 1wt-% to 80wt-%, more preferably 3wt-% to 60wt-% and natural or carbonate synthesis calcium content more more preferably in 5wt-% to 40wt-% scope.
In the next step, in the waterborne suspension containing natural or synthetic calcium carbonate, acid is added.Preferably, this acid have at 25 DEG C 2.5 or be less than 2.5 pK
a.If pK at 25 DEG C
abe 0 or be less than 0, then this acid is preferably selected from sulphuric acid, hydrochloric acid or its mixture.If pK at 25 DEG C
abe 0 to 2.5, then this acid or its slaine are preferably selected from H
2sO
3, HSO
4 -m
+, H
3pO
4, H
2pO
4 -m
+or its mixture, wherein M
+can be Na
+and/or K
+.
In another embodiment, this acid is preferably phosphate combination acetic acid, formic acid or citric acid or its acid salt.
More preferably, this acid is independent phosphoric acid.
These one or more acid can concentrated solution or be added in suspension compared with the form of weak solution.Preferably, H
3o
+ion and mol ratio that is natural or synthetic calcium carbonate are 0.1 to 2.
As a kind of alternative scheme, also before natural or synthetic calcium carbonate suspend, acid can be added in water.
In the next step, or synthetic calcium carbonate natural by carbon dioxide treatment.If use strong acid as sulphuric acid or hydrochloric acid or middle strong acid in the acid treatment of natural or synthetic calcium carbonate, then carbon dioxide is formed automatically.Alternately or additionally, carbon dioxide can be supplied by external source.
The process of acid treatment and use carbon dioxide can be carried out simultaneously, and this is situation when using strong acid.First such as pK can also be used
ain in 0 to 2.5 scope, strong acid carries out acid treatment, subsequently by the carbon dioxide treatment of being supplied by external source.
Preferably, in suspension gaseous carbon dioxide concentration preferably with regard to volume for making ratio (suspension vol): (gaseous state CO
2volume) be 1:0.05 to 1:20, even more preferably 1:0.05 to 1:5.
In a preferred embodiment, acid treatment step and/or carbon dioxide treatment step repeat at least one times, more preferably repeated several times.
After acid treatment and carbon dioxide treatment, the pH of waterborne suspension measured at 20 DEG C naturally reach be greater than 6.0, be preferably greater than 6.5, more preferably greater than 7.0, even more preferably greater than 7.5 value, thus functionalized natural or synthetic calcium carbonate is prepared into pH be greater than 6.0, be preferably greater than 6.5, more preferably greater than 7.0, even more preferably greater than 7.5 waterborne suspension.If make waterborne suspension reach balance, then pH is greater than 7.When the duration sufficient cycle, preferably 1 is little when waterborne suspension is stirred in 10 hours, more preferably 1 to 5 hour, can be adjusted to pH be greater than 6.0 when not adding alkali.
Alternately, before reaching balance (occurring when being greater than 7 at pH), by adding alkali to the value making the pH of waterborne suspension be increased to be greater than 6 after carbon dioxide treatment.Any one traditional alkali can be used, as sodium hydroxide or potassium hydroxide.
Other details about the functionalized natural whiting of preparation is disclosed in WO 00/39222 and US2004/0020410A1, and wherein functionalized natural whiting is described to papermaking filler, and the content of these lists of references is included in subject application at this.
Another different process that preparation is suitable for functionalized natural whiting of the present invention is disclosed in the EP 2 264 108 of same Applicant, and the content of this list of references is included in subject application at this.Substantially, the technique preparing functionalized calcium carbonate in aqueous environments comprises the following steps:
A) at least one is provided to grind natural whiting (GNCC);
B) at least one water soluble acid is provided;
C) gaseous state CO is provided
2;
D) make step this GNCC a) and step b) this acid and step c) this CO
2contact;
It is characterized in that:
(i) step b) each comfortable 20 DEG C of described acid at there is the pKa being greater than 2.5 and being less than or equal to 7 when measuring, described pKa is relevant to the ionization of the first available hydrogen of described acid, and the respective anionic formed when this first available hydrogen loses can form water-soluble Ca salt;
(ii) making after described acid contacts with described GNCC, at least one water soluble salt is provided in addition, its containing under hydrogen salt situation, measure at 20 DEG C time there is the pKa being greater than 7, described pKa is relevant to the ionization of this first available hydrogen, and the anion of described salt can form water-insoluble calcium salt.
Grinding natural whiting is selected from marble, Chalk, calcite, limestone and composition thereof.The suitable particles size of GNCC and water soluble acid can easily see quoted list of references, such as, have the particle of the Weight Median diameter of 0.01 to 10 μm, and be selected from the acid of acetic acid, formic acid, propanoic acid and composition thereof.
Following instance illustrates produces FCC by different parent material.
parent material: limestone
By adding water and there is the d of 3 μm in 20L stainless steel reactor
50non-dispersion stone lime stone (under the wet condition in water, optionally grinding under food stage dispersion or grinding aid (as propylene glycol (MPG)) exist) prepare calcium carbonate suspension, wherein the particle of 33% has the diameter being less than 2 μm, makes the solids content of obtained waterborne suspension count the 16wt% relative to total suspension weight with dry weight.Thereafter make the temperature of this suspension reach and maintain 70 DEG C.Under the about 1000rpm set up making base layer stream stirring, lasting 10 minutes and via separatory funnel, the phosphoric acid in 30% solution form being added in calcium carbonate suspension with the amount corresponding to drying calcium carbonate weight 30 % by weight.After which addition, then stirred suspension 5 minutes.
Make gained suspension hold over night, and FCC has 36m
2the d of the specific surface area of/g and 9.3 μm
50and the d of 23.5 (Malvern)
98(Malvern).
parent material: marble
By adding water and there is the d of 3.5 μm in 20L stainless steel reactor
50do not disperse marble (under the wet condition in water, optionally grinding under food stage dispersion or grinding aid (as propylene glycol (MPG)) exist) prepare calcium carbonate suspension, wherein the particle of 33% has the diameter being less than 2 μm, makes the solids content of obtained waterborne suspension count the 16wt% relative to total suspension weight with dry weight.Thereafter make the temperature of this suspension reach and maintain 70 DEG C.Under the about 1000rpm set up making base layer stream stirring, lasting 10 minutes and via separatory funnel, the phosphoric acid in 30% solution form being added in calcium carbonate suspension with the amount corresponding to drying calcium carbonate weight 30 % by weight.After which addition, then stirred suspension 5 minutes.
Make gained suspension hold over night, and FCC has 46m
2the d of the specific surface area of/g and 9.5 μm
50and the d of 18.9 (Malvern)
98(Malvern).
parent material: marble
By adding water and there is the d of 2 μm in 20L stainless steel reactor
50do not disperse marble (under the wet condition in water, optionally grinding under food stage dispersion or grinding aid (as propylene glycol (MPG)) exist) prepare calcium carbonate suspension, wherein the particle of 48% has the diameter being less than 2 μm, makes the solids content of obtained waterborne suspension count the 16wt% relative to total suspension weight with dry weight.Thereafter make the temperature of this suspension reach and maintain 70 DEG C.Under the about 1000rpm set up making base layer stream stirring, lasting 10 minutes and via separatory funnel, the phosphoric acid in 30% solution form being added in calcium carbonate suspension with the amount corresponding to drying calcium carbonate weight 50 % by weight.After which addition, then stirred suspension 5 minutes.
Make gained suspension hold over night, and FCC has 71m
2the d of the specific surface area of/g and 10.6 μm
50and the d of 21.8 (Malvern)
98(Malvern).
Similarly, functionalized winnofil is obtained.As obtained in detail in the EP 2070991B1 of same Applicant, wherein functionalized winnofil obtains by the following method: make winnofil and H in an aqueous medium
3o
+ion and to be dissolved in aqueous medium and the anion contact of water-fast calcium salt can be formed, to form the slurry of functionalized winnofil, wherein this functionalized winnofil is included in the calcium salt of insoluble at least part of crystallization of this anion that the surface of at least part of winnofil is formed.
This dissolving calcium ion corresponds to relative to due to H
3o
+ion-solubility winnofil and the Excessive lysis calcium ion of spontaneous dissolving calcium ion, wherein this H
3o
+ion only provides with the counter ion counterionsl gegenions form of anion (also namely via the anion of adding in acid or non-calcium acid addition salt), and there is not other calcium ion any or calcium ion generation source.
This Excessive lysis calcium ion preferably by interpolation soluble neutral or acid calcium salt, or by adding original position and produce the acid of soluble neutral or acid calcium salt or the neutral or non-calcium salt of acid providing.
This H
3o
+ion by adding the acid salt of acid or this anion, or provides in order to the acid or acid salt providing this Excessive lysis calcium ion all or part of while of interpolation.
In a kind of preferred embodiment of the functionalized natural or synthetic calcium carbonate of preparation, make natural or synthetic calcium carbonate at least one be selected from following compound exist under with acid and/or carbon dioxide reaction: aluminum sulfate, silicate, silicon dioxide, aluminium hydroxide, alkaline earth aluminate (as sodium aluminate or potassium aluminate), magnesium oxide or its mixture.Preferably, this at least one silicate is selected from aluminium silicate, calcium silicates or alkaline-earth-metal silicate.These components can be added in the waterborne suspension comprising natural or synthetic calcium carbonate before interpolation acid and/or carbon dioxide.
Alternately, silicate and/or silicon dioxide and/or aluminium hydroxide and/or alkaline earth aluminate and/or magnesia components can start to be added into when reacting in the waterborne suspension of natural or synthetic calcium carbonate in natural or synthetic calcium carbonate and acid and carbon dioxide.Being disclosed in WO 2004/083316 about preparing functionalized other details that is natural or synthetic calcium carbonate under existing at least one silicate and/or silicon dioxide and/or aluminium hydroxide and/or alkaline earth aluminate component, being included in subject application in this content by this list of references.
Functionalized natural or synthetic calcium carbonate maintenance suspension can be made, make its further stabilisation optionally by dispersant.Traditional dispersant well known by persons skilled in the art can be used.Preferred dispersants is polyacrylic acid, or the polyacrylic acid partially or completely neutralized.
Alternately, can dry above-mentioned waterborne suspension, obtain thus in pellet or the solid of powder type (also namely dry or containing the little water not in fluid form) functionalized natural or synthetic calcium carbonate.
In a preferred embodiment, functionalized natural or synthetic calcium carbonate has 5m
2/ g to 200m
2/ g, preferably 20m
2/ g to 150m
2/ g, more preferably 40m
2/ g to 100m
2the BET specific surface area of/g, by using nitrogen and measuring according to the BET method of ISO 9277:2010.
In addition preferably, functionalized natural or synthetic calcium carbonate has 0.1 μm to 50 μm, preferably 0.5 μm to 25 μm, more preferably 0.8 μm to 20 μm, the more more preferably Weight Median particle diameter of 1 μm to 15 μm, measures by using the long bed of Malvern Mastersizer X (MalvernMastersizer X long bed).
In a preferred embodiment, functionalized natural or synthetic calcium carbonate (FCC) has 5m
2/ g to 200m
2bET specific surface area within the scope of/g and 0.1 μm are to the Weight Median particle diameter within the scope of 50 μm.More preferably, specific surface area is at 20m
2/ g to 150m
2within the scope of/g and Weight Median particle diameter at 0.5 μm within the scope of 25 μm.Even more preferably, specific surface area is at 40m
2/ g to 100m
2within the scope of/g and Weight Median particle diameter at 1 μm within the scope of 15 μm.
By above-mentioned technique, natural or synthetic calcium carbonate is modified, thus improves the porosity of FCC on the one hand and increase surface area on the other hand.Compared to traditional calcium carbonate, this FCC with more rapid rate water suction, and compares the fluid of traditional calcium carbonate energy more than enough absorption ten times.With reference to people " Modified calcium carbonate coatings with rapid absorption andextensive liquid uptake capacity " such as CJ.Ridgway, Colloids and Surfaces A:Physicochemical and Engineering Aspects, 236th volume, No. 1-3,91-102 page, in April, 2004.
In this respect, it is believed that because in the hole of functionalized calcium carbonate and structure between hole, so by air capture in hole, this facilitate particle floating.
Preferably, functionalized natural or synthetic calcium carbonate has the intraparticle porosity in 20vol.-% to 99vol.-%, preferably 30vol.-% to 70vol.-%, more preferably 40vol.-% to 60vol.-% scope, and this intraparticle porosity calculates according to mercury porosimetry measured value.According to bimodal derivative pore size distribution curve, peak-to-peak minimum point indicates in separable particle and the diameter of pore volume between particle.The pore volume that diameter is greater than this diameter is the pore volume relevant to hole between particle.Total pore size volume deducts pore volume between this particle and obtains particle void volume, intraparticle porosity can be calculated by particle void volume, preferably with point rate form of solid material volume, described in Transport in Porous Media (2006) 63:239-259.
Thus, the intraparticle porosity determined with pore volume/unit cell bulk form is in 20vol.-% to 99vol.-%, preferably 30vol.-% to 80vol.-%, more preferably 40vol.-% to 70vol.-%, most preferably 50vol.% to 65vol.% scope.
Due to the high porosity of functionalized natural or synthetic calcium carbonate, on side, large quantity of air is present in hole, and when contacting with gastric juice, this large quantity of air is replaced, and water and gastric juice enter in hole, and the not controlled decomposition of functionalized natural or synthetic calcium carbonate may be started, discharge CO thus
2.For preventing not controlled dissolution and water and/or gastric juice from entering in hole, functionalized natural or synthetic calcium carbonate is mixed with at least one formulation aid.This formulation aid is at least one film forming compound and/or compositions.This compound and/or compositions can be selected from hydrophilic film excipient or be selected from lipotropy film forming excipient and combination thereof, and the amount existed is that about 1wt% to about 60wt%, preferably about 3wt% are to about 60wt%, more preferably from about 5wt% to about 60wt% based on preparaton total weight.
The hydrophilic film excipient producing hydrophilic formulation includes but not limited to water-soluble polyethylene glycol, polyethylene glycol oxide, polypropylene glycol, polypropylene oxide or its combination, and described polymer has 2,000Da to 20, the weight average molecular weight of 000,000Da, chitosan, acrylic acid polymer, polyvinylpyrrolidone and modifier (insoluble crospolyvinylpyrrolidone thereof, the homopolymer of NVP), modified cellulose gum, glycolic starch, pregelatinized starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, alkylcellulose ester, hydroxy alkyl cellulose ester, carboxyl alkyl cellulose ester, hydroxypropylmethyl cellulose phthalate, carboxymethyl cellulose salt, alginate, ion exchange resin, natural gum, chitin, clay, gellan gum, crosslinked Po Lakelin (polacrillin) copolymer, agar, gelatin, dextrin, Lac and combination thereof.
The lipotropy film forming excipient producing lipotropy preparaton includes but not limited to hydrogenated vegetable oil, Oleum Ricini, mineral oil, and carbon chain lengths is C
6to C
20wax fatty acid and soap, it is branching, non-branching, unsaturated, fractional saturation, and its combination, magnesium stearate and/or calcium stearate, paraffin, the polyglycol ether of spermol, cetearyl alcohol, glyceryl monostearate, lanoline, lanolin alcohol, alphanol, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, poly-stearic acid ethylidene ester, sorbitan ester, stearyl alcohol, dibehenolin, sodium stearyl fumarate, glycerol distearate and combination thereof.
At once floating gastric retention preparaton of the present invention optionally comprises at least one water soluble acid further.This water soluble acid is preferably selected from the acid in solid form, as citric acid, fumaric acid, tartaric acid or malic acid and combination thereof.The amount of this acid or its combination based on preparaton total weight be 10wt% at the most, be preferably at the most 8wt%, be more preferably 5wt% at the most.
Make thus obtained preparaton experience pressing process, wherein functionalized natural or synthetic calcium carbonate, at least one active constituents of medicine or nonactive presoma, formulation aid and optional water soluble acid are made granule.This granulating technique can be selected from melting, dry type or wet granulation technique, and roll, extrusion spheronization or hot-melt extruded.Due to the water sensitivity of acid, non-water based granulation liquid is preferably used to carry out wet granulation.This non-water based granulation liquid is such as 96% ethanol.
The granule obtained by arbitrary above-mentioned granulating technique is floating gastric retention granule at once.This kind of granule can directly administration when being packaged in medicated bag or bar-shaped bag.Described granule also can repressed one-tenth tablet or micro tablet or pill.Another kind of dosage form is capsule form.
Be not bound by any theory, the present inventor believes, granule comprises functionalized natural or synthetic calcium carbonate, be mixed with film former and this optional solid, water soluble acid, hole is capped or cover at least partly, closed or part is closed, thus by air entrapment in hole, improve the floatability of granule thus.
The water soluble acid of optional interpolation is intended to provide H+ donor when contacting with gastric juice.It is believed that this H+ donor supports flotation property as follows.Hole is that air rubber capsule is contained in closed or that part is closed hole by the functionalized natural or synthetic calcium carbonate partially or completely closed.
When contacting with gastric juice, there is the partial corrosion of functionalized natural or synthetic calcium carbonate, and can release portion entrapped air plug.But due to extra H+ donor, therefore functionalized natural the or synthetic calcium carbonate of part decomposes further, disengages CO thus
2, this CO
2the air that Some substitute discharges in vent plug.Thus, even if also can support floating just in the case of corrosion in granule.
When granule is pressed into tablet, because the enterable surface of gastric juice is less, this effect weakens.Because film forming compound and/or compositions part protection hole can not because of gastric juice and/or water excessive corrosion, so tablet will continue to float on gastric juice enough long-time under one's belt.Even if the hole on surface is corroded and is filled with fluid, buoyancy is not still because protection bottom hole is kept by the film forming compound of premature corrosion and/or compositions.
In a particular embodiment, floating gastric retention preparaton is tablet form at once.This tablet comprises other compound further, as filler, binding agent, diluent, binding agent, lubricant or hybrid materials, as buffer agent and adsorbent, natural or synthesis flavouring agent, natural or synthesis flavoring agent, natural or synthetic coloring matter, natural or synthetic sweetener and/or its mixture.
Suitable natural or synthesis flavouring agent comprises one or more mankind or other animal volatile compound by detected by scent with extremely low concentration usually.
Suitable natural or synthesis flavoring agent includes but not limited to Herba Menthae; as Mentha arvensis L. syn.M.haplocalyxBrig, menthol, Rhizoma et radix valerianae, Cortex Cinnamomi, various flavoring agent of fruit; exist with individual or mixed form; quintessence oil, as thymol, eucalyptol, menthol and methyl salicylate, pi-allyl pyrazine, methoxypyrazine, 2-isobutyl-3-methoxypyrazine, acetyl group-L-pyrazine, 2-acetoxyl group pyrazine, aldehyde, alcohol, ester, ketone, pyrazine, phenolic resins, terpenoid and composition thereof.
The use amount of flavoring agent usually depends on individual flavor variations and can such as in about 0.5 % by weight to about 4 % by weight scope of final composition.
Suitable natural or synthetic coloring matter includes but not limited to titanium dioxide, flavone dye, isoquinolin dyestuff, polyenoid coloring agent, pyrans coloring agent, naphthoquinone dyestuff, quinone and anthraquinone dye, chromene dyestuff, Benzofurantone dyestuff and indigo dye and indole coloring agent.The example is that caramel is painted, roucou, CHLOROPHYLLINE, alkermes, betanin, Rhizoma Curcumae Longae, Stigma Croci, Fructus Capsici, lycopene, Ban Lan and Folium Clitoriae ternateae.
Suitable natural or synthetic sweetener includes but not limited to xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar, maltose, boiling starch or corn-syrup solids and sugar alcohol, as sorbitol, xylitol, mannitol and composition thereof; Water-soluble artificial sweeting agent, namely as soluble sugar refined salt (also sodium or calcium saccharin salt), Sai Kelamei salt, acesulfame potassium and analog, and the glucide of free acid form and aspartame base sweeting agent, as L-aspartyl-phenylalanine methyl ester,
or
Generally speaking, the amount of sweeting agent will be used for the aequum change of the sweeting agent of specific tablets compositions with selection.
In background of the present invention, active constituents of medicine refers to the active constituents of medicine into synthetic source, semi-synthetic source or natural source or its combination.This active component is also contained the nonactive pharmacy that activates at subsequent stage and eobiont body.
The activation of this kind of nonactive presoma is known to those skilled in the art and be generally used for such as activating in stomach and/or gastrointestinal channel, as acidic activated or Trypsin enzymolysis or chymotrypsin protein enzymolysis.
It will be appreciated by persons skilled in the art that mentioned activation method only has illustrative aspects, and be not intended to that there is restricted feature.
The invention still further relates to a kind of technique or method of producing floating gastric retention preparaton at once, comprise the following steps:
A) mineral containing functionalized natural and/or synthetic calcium carbonate are provided, wherein this functionalized natural or synthetic calcium carbonate is natural or synthetic calcium carbonate and carbon dioxide and one or more acid product, and wherein this carbon dioxide is formed by acid treatment original position and/or supplied by external source;
B) at least one active constituents of medicine is provided;
C) at least one formulation aid is provided;
D) blend step a), b) and c) in the compound that provides;
E) granulation step d) mixture.
At once the granulation of floating gastric retention preparaton is also undertaken by rolling.
In the method for the invention, the natural whiting source for the preparation of this functionalized calcium carbonate (FCC) is selected from marble, calcite, Chalk, limestone and dolomite and/or its mixture.
In a particular embodiment, synthetic calcium carbonate for the preparation of this functionalized calcium carbonate is winnofil (PCC), comprise aragonitic, vaterite-type or calcite type mineral crystal form, especially prismatic, rhombohedron shape or scalenohedron shape PCC or its mixture.
For the functionalized natural of the inventive method or synthetic calcium carbonate, there is 5m
2/ g to 200m
2/ g, preferably 20m
2/ g to 150m
2/ g, more preferably 40m
2/ g to 100m
2the BET specific surface area of/g, by using nitrogen and measuring according to the BET method of ISO 9277:2010.
In addition preferably, functionalized natural or synthetic calcium carbonate in the inventive method has 0.1 to 50 μm, preferably 0.5 to 25 μm, more preferably 0.8 to 20 μm, the more more preferably Weight Median particle diameter of 1 to 15 μm, measures by using the long bed of Malvern Mastersizer X.
In the method for the invention, at least one active constituents of medicine or nonactive presoma are selected from synthetic source, semi-synthetic source or natural source or its combination.
The activation of this kind of nonactive presoma is known to those skilled in the art, and be generally used for such as activating in stomach and/or gastrointestinal channel, as acidic activated, alkaline activation, trypsin activated, the chymotrypsin protein enzyme activation reached by enzymatic lysis or pepsinogen activation.
Method of the present invention also can change as follows: first make step c) part formulation aid and step FCC a) and step b) at least one active constituents of medicine mix; and subsequently the remainder of formulation aid is added in mixture, then carry out granulation step e).
In the method for the invention, at least one formulation aid is at least one film forming compound and/or compositions.
This compound and/or compositions can be selected from hydrophilic film excipient or be selected from lipotropy film forming excipient and combination thereof, and exist to about 60wt%, more preferably from about 5wt% to the amount of about 60wt% to be about 1wt% to about 60wt%, preferably about 3wt% based on preparaton total weight.
The hydrophilic film excipient producing hydrophilic formulation includes but not limited to water-soluble polyethylene glycol, polyethylene glycol oxide, polypropylene glycol, polypropylene oxide or its combination, and described polymer has 2,000Da to 20, the weight average molecular weight of 000,000Da, chitosan, acrylic acid polymer, polyvinylpyrrolidone and modifier (insoluble crospolyvinylpyrrolidone thereof, the homopolymer of NVP), modified cellulose gum, glycolic starch, pregelatinized starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, alkylcellulose ester, hydroxy alkyl cellulose ester, carboxyl alkyl cellulose ester, hydroxypropylmethyl cellulose phthalate, carboxymethyl cellulose salt, alginate, ion exchange resin, natural gum, chitin, clay, gellan gum, crosslinked Po Lakelin copolymer, agar, gelatin, dextrin, Lac and combination thereof.
The lipotropy film forming excipient producing lipotropy preparaton includes but not limited to hydrogenated vegetable oil, Oleum Ricini, mineral oil, and carbon chain lengths is C
6to C
20wax fatty acid and soap, it is branching, non-branching, unsaturated, fractional saturation, and its combination, magnesium stearate and/or calcium stearate, paraffin, the polyglycol ether of spermol, cetearyl alcohol, glyceryl monostearate, lanoline, lanolin alcohol, alphanol, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, poly-stearic acid ethylidene ester, sorbitan ester, stearyl alcohol, dibehenolin, sodium stearyl fumarate, glycerol distearate and combination thereof.
In the method for the invention, can step a), b) and/or c) in add water soluble acid, also namely in steps d) before add water soluble acid.In a kind of ad hoc approach, can in step a), b) and/or c) middle portioning interpolation water soluble acid.
This acid with based on preparaton total weight at the most 10wt%, preferably at the most 8wt%, more preferably the amount of 5wt% exists at the most again.
This water soluble acid is preferably selected from the acid in solid form, as citric acid, fumaric acid, tartaric acid or malic acid and combination thereof.
The invention still further relates to the purposes of mineral in floating gastric retention preparaton at once containing functionalized natural or synthetic calcium carbonate.This kind of preparaton is made dosage form, comprises tablet, micro tablet, granule, capsule or pill.
The invention further relates to mineral containing functionalized natural or synthetic calcium carbonate for the preparation of the purposes in the technique of floating gastric retention preparaton at once or method.This kind of preparaton is made dosage form, comprises tablet, micro tablet, granule, capsule or pill.
The invention further relates to the functionalized natural or purposes of synthetic calcium carbonate in floating gastric retention preparaton at once as described earlier.
The present invention also relates to the purposes of functionalized natural or synthetic calcium carbonate for the preparation of floating gastric retention preparaton at once further.
The present invention relates to the tablet, micro tablet, granule, capsule or the pill that comprise floating gastric retention preparaton at once of the present invention more further.
The present invention relates to further and comprises this tablet of floating gastric retention preparaton, micro tablet, granule, capsule or pill at once, and wherein this preparaton is obtained by method described herein.
Accompanying drawing explanation
Now explain the present invention further by the following drawings and embodiment, described drawings and Examples are only illustrative, are not intended to limit the present invention by any way.
Fig. 1 a is the schematic diagram of the proposed stomach model method for assessment of floating behavior and drug release.
Fig. 1 b is the schematic diagram of the individual unit of Fig. 1 a.
Fig. 2 shows the small size of floating preparaton HF1 and LF2 and the caffeine release characteristic of standard size tablet.
Fig. 3 shows the comparison of the caffeine release characteristic of the standard size floating tablet using stomach model and USP dissolver II to test.
Detailed description of the invention
Embodiment
prepare the floating preparaton based on FCC
Floating gastric retention preparaton at once of the present invention is prepared according to table 1.
For hydrophilic formulation (HF1), weigh up FCC, water-soluble poly ethylene oxide (Polyox
tMwSR 301, derives from Dow Chemical company, USA), low substituted hydroxy-propyl methylcellulose (
100 Premium LV, derive from Switzerland SandozPharma AG) and citric acid (Acid citricum monohydr.purvis,
aG, Switzerland) and (Coffeiunm WSF, derives from as the caffeine of model drug
germany) aequum, and at room temperature in barrel mixer (Turbula, model T2C, Switzerland), mix 10 minutes with 33rpm.Then, ethanol (96%) is added as granulation liquid.Granulating technique is carried out by slurried in beaker.Add ethanol until material becomes stable homogenizing slurry.Dry gained slurry and making its sieve (1000 μm).
For lipotropy preparaton (LF2), weigh up FCC, water-soluble poly ethylene oxide (Polyox
tMwSR 301, derives from Dow Chemical company, USA), hydrogenated vegetable oil (
jRS Pharam, Germany) and the aequum of caffeine as model drug.Before using, will
melting.Add the melting of FCC, caffeine and half under agitation
then, under magnetic stirrer, add PolyoxTMWSR 301 and remaining half
when cooling through stirring material, because original position is coalescent and obtain granule.
Gained granule is made to sieve (1000 μm).
The composition of table 1. floating composition
preparation is containing the tablet based on the floating preparaton of FCC
Floating gastric retention tablet is at once prepared by using one-shot head eccentric press (Korsch EK0, Germany) compacting based on floating preparaton HF1 and LF2 of FCC according to table 2.Calculating gained tablet height, obtains hydrophilic and lipotropy preparaton density is respectively 0.8g/cm
3and 0.9g/cm
3.The drift gap of pressing process is set as respectively the value of calculation of HF and LF preparaton.Manufacture the tablet of two kinds of sizes: standard size and small size.Small size compacting thing is used as micro tablet, and (also namely diameter is less than 3mm
1tablet) model.Standard size tablet is plane, and small size tablet has spill.
The preparation of table 2. floating tablet
Further tablet is characterized, and result is summarized in table 3.
The performance of the floating tablet that table 3. produces
assess external floating behavior and drug release
For assessing external buoyant characteristic and the drug release (n=4) of tablet simultaneously, use dissolver (the Sotax AT7smart improved according to the schematic diagram in Fig. 1, Switzerland) (be also about to 4 containers and change Erlenmeyer 500ml flask into), wherein experimental facilities (Fig. 1) is made up of 4 the Merlon Erlenmeyer flasks (500ml) be fixed on the bracket of water bath chader (the accurate Celsius temperature processor 345 of Kobrin Scientific, Switzerland).Bracket moves horizontally, with the rotary speed of 75rpm and the amplitude of 50mm.At 37 DEG C of temperature, use 400ml 0.1N HCl to measure as tested media.
In order to compare, USP dissolver II (Sotax AT 7smart, Switzerland) is used to analyze floating behavior and drug release (n=3).Measure in 900ml 0.1N HCl under the oar rotational case of 100rpm and at 37 ± 0.5 DEG C of temperature.
Ultraviolet/visible spectrophotometer (Perkin Elmer Lambda 25, USA) is used in dissolve medium, to analyze medicament contg with predetermined time interval under 272nm.The UV absorption spectrum of caffeine represents and reaches peak value at 205nm and 273nm place a pair and the absorption band with characteristic absorption shoulder therebetween.
Typically, content of caffeine is determined close to the absorbance at 273nm peak by measuring.
Be defined as floating time delay of reference tablet after tablet put into tested media and rise to the time needed for tested media surface, and the tablet that is defined as naked-eye observation of floating persistent period floats on the total time on tested media surface continuously.
The caffeine release characteristic of the floating tablet of hydrophilic and lipotropy preparaton is presented in Fig. 2.The standard size tablet of two kinds of preparatons all represents floatability at once.When preparaton HF1, the floating 5h of compacting thing, and corrode completely within this time while release medicinal material, and keep floating.For lipotropy preparaton LF2, observe that the flotation time is some days.After model drug discharges completely, remaining lipotropy substrate.The mechanisms for drug release of the floating preparaton of two types is different: preparaton HF1 is corrosion control, and hydrophobicity preparaton LF2 is diffusion control.For hydrophilic floating tablet, caffeine all discharges after 5h, and for lipotropy preparaton, after 59 hours 45 minutes, complete drug release detected.
Fig. 2 shows the drug release characteristics of the small size floating tablet of preparaton HF1 and LF2 further.Two kinds of preparatons all do not observe floating time delay.For the compacting thing of hydrophilic formulation HF1, measure the flotation time of 90 minutes, and tablet dissolves completely.Mechanisms for drug release classifies as corrosion control; 100% caffeine release is reached after 90 minutes.Small size tablet floating some days of preparaton LF2, and leave lipotropy tablet matrix.Drug release is diffusion control; After 17h, medical substance discharges completely.Small size floating tablet disintegrate when the release characteristic (Fig. 2) of preparaton LF2 is presented at 210 minutes.
the comparison of stomach model and USP dissolver II
Fig. 3 compares the drug release of the floating tablet using customization stomach model (schematic diagram of stomach model device is shown in Fig. 1) and traditional USP dissolver II to measure.The dissolving test undertaken by USP stirring paddle method causes caffeine to discharge deceleration; 100% medical substance discharged after 470 minutes.During measuring, the tablet based on FCC swims in tested media on the surface and rotate around stirring paddle axle.Use stomach model method, in the complete caffeine release of the standard size tablet of 300 minutes later evaluation preparaton HF1.Due to moving horizontally of agitator, floating tablet is immersed in dissolve medium completely, and avoids tablet surface to become dry.
based on the vitro drug release of the floating tablet of FCC
Testing in vitro based on the tablet of FCC shows, and likely manufactures the floating tablet with different release characteristic.Small size tablet discharges medicine quickly.This can be explained by its higher surface area.Observe further, dimensional effect and preparaton type (being also lipotropy or hydrophilic) have nothing to do.When the agent of hydrophilic tablet formulation, there is not disintegrate; This supports the hypothesis of corrosion control mechanisms for drug release.The disintegrate 210 minutes time of small size lipotropy tablet.The change of release characteristic supports the hypothesis of the diffusion control mechanism from lipotropy preparaton.
for the preparation of the FCC of floating tablet
It seems that FCC be the promising novel drugs excipient of one preparing floating tablet.Due to its high porosity and laminar surface, likely produce density and be less than one and at once floating compacting thing.Prepared floating tablet does not show floating time delay, and because this reducing the risk of unpredictable and too early gastric emptying.In addition, show based on the floating tablet of FCC damage that enough hardness causes due to gastric peristalsis with opposing and can process further.
Two kinds of floating preparaton-hydrophilic and hydrophobic are prepared.According to the result of preliminary test, it seems that granulation step be that production is necessary based on the floating preparaton of FCC, to improve mobility and the fillibility that mixture enters the mould of tablet machine.
Caffeine release characteristic demonstrates, and the lipotropy of preparaton affects drug release rate and mechanisms for drug release.Tablet sizes affects drug release rate, but does not affect releasing mechanism.
customization stomach model
Stomach model demonstrates the circumscribed good performance overcoming standard method.Due to the continuous jolting of dissolution vessel, floating tablet is not dry from the teeth outwards.The shortage of spinner member eliminates the effect observed in USP dissolver I and II.In addition, under not needing to force tablet to be in liquid surface, because this simplify the structure of stomach model.At test period, dissolve medium protection tablet is not by the remarkable impact of solid-state construction element.
Compared to the traditional dissolution in vitro test undertaken by USP device I or II, the stomach model proposed provides the probability studying the drug release of floating delivery apparatus when considering gastric peristalsis.Therefore conclusion is, this new method is likely with the in vivo behavior of high accuracy prediction floating tablet.
Measuring method
True density
The true density of FCC is measured by helium hydrometry (Micromeritics AccuPyc 1330, USA).
BET specific surface area
For measuring specific surface area, Nova 2000e (Quantachrome Instruments, USA) is used together with 5 BET methods.At room temperature make sample after degassed 12 hours, under steady temperature (77.4K), use radon survey sample.Carry out twice measurement.
Particle size distribution
The long bed of Mastersizer X (Malvern Instruments, UK) is used to measure particle size distribution.By FCC particle dispersion in isopropyl myristate, and then by using small samples display unit (Malvern Instruments, UK) (difference) analysis.Carry out three times to sample to measure.
Based on the sign of the floating tablet of FCC
Electronic balance (Mettler Toledo AX204Delta Range, Switzerland) is used to measure Average tablet weight (n=7).Usage degree disk indicator (Mitutoyo Model CD-15CPX, Japan) measures tablet diameters (n=7) and tablet thickness (n=7).Carry out helium hydrometry (Micromeritics AccuPyc 1330, USA) and measure true density.Porosity ε according to following equation (1) Calculation Plane tablet:
Wherein m is tablet weight, and ρ is the true density of mixture of powders, and r is tablet radius, and h is tablet height.The porosity ε of spill compacting thing calculates as follows:
Wherein m is tablet weight, and ρ is the true density of mixture of powders, and r is tablet radius, cylinder thickness centered by w, and h
capfor the height of spherical cap.
Hardness-testing device (Tablet Tester 8M, Switzerland) is used to analyze tablet fracture strength (n=3).Then, respectively according to the tablet tensile strength σ (MPa) of equation 3 and 4 Calculation Plane and concave tablets.
Wherein F is radial crushing force, and d is tablet diameters, and h is tablet height.
Wherein F is radial crushing force, and d is tablet diameters, and h is tablet height, and cylinder thickness centered by w.
Ultraviolet/visible light is measured
Ultraviolet/visible spectrophotometer (Perkin Elmer Lambda 25, USA) is used to carry out on-line analysis with predetermined time interval to the medicament contg in dissolve medium under 272nm.The UV absorption spectrum of caffeine shows a pair absorption band, and it reaches peak value at 205nm and 273nm place and has characteristic absorption shoulder therebetween.Typically, content of caffeine is determined close to the absorbance at 273nm peak by measuring.
Claims (35)
1. floating gastric retention preparaton at once, it comprises at least one containing the mineral of functionalized natural and/or synthetic calcium carbonate and at least one active constituents of medicine and at least one formulation aid, wherein this functionalized natural or synthetic calcium carbonate is natural or synthetic calcium carbonate and carbon dioxide and one or more acid product, and wherein this carbon dioxide is formed by acid treatment original position and/or supplied by external source.
2. preparaton according to claim 1, the natural whiting source wherein for the preparation of this functionalized calcium carbonate (FCC) is selected from marble, calcite, Chalk, limestone or dolomite and/or its mixture.
3. preparaton according to claim 1, synthetic calcium carbonate wherein for the preparation of this functionalized calcium carbonate is winnofil (PCC), comprise aragonitic, vaterite-type or calcite type mineral crystal form, especially prismatic, rhombohedron shape or scalenohedron shape or its mixture.
4. according to the preparaton of any one of claim 1-3, wherein this acid is selected from hydrochloric acid, sulphuric acid, sulfurous acid, disulfate, phosphoric acid, phosphate combination acetic acid, formic acid or citric acid or its acid salt, and composition thereof, be preferably phosphoric acid.
5., according to the preparaton of any one of claim 1-4, wherein this functionalized natural or synthetic calcium carbonate has 5m
2/ g to 200m
2/ g, preferably 20m
2/ g to 150m
2/ g, more preferably 40m
2/ g to 100m
2the BET specific surface area of/g, by using nitrogen and measuring according to the BET method of ISO 9277:2010.
6. according to the preparaton of any one of claim 1-5, wherein this functionalized natural or synthetic calcium carbonate has 0.1 μm to 50 μm, preferably 0.5 μm to 25 μm, more preferably 0.8 μm to 20 μm, the more more preferably Weight Median particle diameter of 1 μm to 15 μm, measures by using the long bed of MalvernMastersizer X.
7., according to the preparaton of any one of claim 1-6, wherein this at least one active constituents of medicine or nonactive presoma are selected from synthetic source, semi-synthetic source or natural source or its combination.
8., according to the preparaton of any one of claim 1-7, wherein this at least one formulation aid is selected from film forming compound and/or compositions.
9. preparaton according to claim 8, wherein this film forming compound and/or compositions can be selected from hydrophilic film excipient or be selected from lipotropy film forming excipient or its combination.
10. preparaton according to claim 9, wherein this hydrophilic film excipient is selected from water-soluble polyethylene glycol, polyethylene glycol oxide, polypropylene glycol, polypropylene oxide or its combination, and described polymer has 2,000Da to 20, the weight average molecular weight of 000,000Da, chitosan, acrylic acid polymer, polyvinylpyrrolidone and modifier (insoluble crospolyvinylpyrrolidone thereof, the homopolymer of NVP), modified cellulose gum, glycolic starch, pregelatinized starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, alkylcellulose ester, hydroxy alkyl cellulose ester, carboxyl alkyl cellulose ester, hydroxypropylmethyl cellulose phthalate, carboxymethyl cellulose salt, alginate, ion exchange resin, natural gum, chitin, clay, gellan gum, crosslinked Po Lakelin copolymer, agar, gelatin, dextrin, Lac and combination thereof.
11. preparatons according to claim 9, wherein this lipotropy film forming excipient is selected from hydrogenated vegetable oil, Oleum Ricini, mineral oil, carbon chain lengths is wax fatty acid and the soap of C6 to C20, it is branching, non-branching, unsaturated, fractional saturation, and its combination, magnesium stearate and/or calcium stearate, paraffin, spermol, cetearyl alcohol, glyceryl monostearate, lanoline, lanolin alcohol, the polyglycol ether of alphanol, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, poly-stearic acid ethylidene ester, sorbitan ester, stearyl alcohol, dibehenolin, sodium stearyl fumarate, glycerol distearate and combination thereof.
12. according to the preparaton of any one of claim 1-11, and it comprises water-soluble solid acid further.
13. preparatons according to claim 12, wherein this water-soluble solid acid is selected from citric acid, fumaric acid, tartaric acid or malic acid and combination thereof.
14. methods of producing floating gastric retention preparaton at once, comprise the following steps:
Mineral (FCC) containing functionalized natural or synthetic calcium carbonate a) are provided, wherein this functionalized natural or synthetic calcium carbonate is natural or synthetic calcium carbonate and carbon dioxide and one or more acid product, and wherein this carbon dioxide is formed by acid treatment original position and/or supplied by external source;
B) at least one active constituents of medicine is provided;
C) at least one formulation aid is provided;
D) by step a), b) and c) in provide compound mixing;
E) by means of melting, dry type or wet granulation or roll steps d) in obtain mixture granulation.
15. methods according to claim 14; wherein first by step c) part formulation aid and step FCC a) and step b) at least one active constituents of medicine mix; and subsequently the remainder of this formulation aid is added in mixture, then carry out granulation step e).
16. according to the method for claims 14 or 15, and the natural whiting source wherein for the preparation of this functionalized calcium carbonate (FCC) is selected from marble, calcite, Chalk, limestone and dolomite and/or its mixture.
17. according to the method for claims 14 or 15, synthetic calcium carbonate wherein for the preparation of this functionalized calcium carbonate is winnofil (PCC), comprise aragonitic, vaterite-type or calcite type mineral crystal form, especially prismatic, rhombohedron shape or scalenohedron shape PCC or its mixture.
18. according to the method for claim 14-17, and wherein this acid is selected from hydrochloric acid, sulphuric acid, sulfurous acid, disulfate, phosphoric acid, phosphate combination acetic acid, formic acid or citric acid or its acid salt, and composition thereof, be preferably phosphoric acid.
19. according to the method for any one of claim 14-18, and wherein this functionalized natural or synthetic calcium carbonate has 5m
2/ g to 200m
2/ g, preferably 20m
2/ g to 150m
2/ g, more preferably 40m
2/ g to 100m
2the BET specific surface area of/g, by using nitrogen and measuring according to the BET method of ISO 9277:2010.
20. according to the method for any one of claim 14-19, wherein this functionalized natural or synthetic calcium carbonate has 0.1 μm to 50 μm, preferably 0.5 μm to 25 μm, more preferably 0.8 μm to 20 μm, the more more preferably Weight Median particle diameter of 1 μm to 15 μm, measures by using the long bed of MalvernMastersizer X.
21. according to the method for any one of claim 14-20, and wherein this at least one active constituents of medicine or nonactive presoma are selected from synthetic source, semi-synthetic source or natural source or its combination.
22. according to the method for any one of claim 14-21, and wherein this at least one formulation aid is at least one film forming compound and/or compositions.
23. methods according to claim 22, wherein this at least one film-forming composition is selected from hydrophilic film excipient or is selected from lipotropy film forming excipient and combination thereof.
24. methods according to claim 23, wherein this hydrophilic film excipient comprises water-soluble polyethylene glycol, polyethylene glycol oxide, polypropylene glycol, polypropylene oxide or its combination, and described polymer has 2,000Da to 20, the weight average molecular weight of 000,000Da, chitosan, acrylic acid polymer, polyvinylpyrrolidone and modifier (insoluble crospolyvinylpyrrolidone thereof, the homopolymer of NVP), modified cellulose gum, glycolic starch, pregelatinized starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, alkylcellulose ester, hydroxy alkyl cellulose ester, carboxyl alkyl cellulose ester, hydroxypropylmethyl cellulose phthalate, carboxymethyl cellulose salt, alginate, ion exchange resin, natural gum, chitin, clay, gellan gum, crosslinked Po Lakelin copolymer, agar, gelatin, dextrin, Lac and combination thereof.
25. methods according to claim 23, wherein this lipotropy film forming excipient comprises hydrogenated vegetable oil, Oleum Ricini, mineral oil, carbon chain lengths is wax fatty acid and the soap of C6 to C20, it is branching, non-branching, unsaturated, fractional saturation, and its combination, magnesium stearate and/or calcium stearate, paraffin, spermol, cetearyl alcohol, glyceryl monostearate, lanoline, lanolin alcohol, the polyglycol ether of alphanol, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, poly-stearic acid ethylidene ester, sorbitan ester, stearyl alcohol, dibehenolin, sodium stearyl fumarate, glycerol distearate and combination thereof.
26. according to the method for any one of claim 23-25, and wherein the amount of this film forming excipient is about 1wt% to about 60wt% based on this preparaton total weight, is preferably about 3wt% to about 60wt%, is more preferably about 5wt% to about 60wt%.
27. according to the method for any one of claim 14-26, wherein in steps d) before add water soluble acid.
28. methods according to claim 27, wherein this water soluble acid is preferably selected from the acid in solid form, as citric acid, fumaric acid, tartaric acid or malic acid and combination thereof.
29. methods according to claim 28, the amount of wherein this acid or its combination based on this preparaton total weight be 10wt% at the most, be preferably at the most 8wt%, be more preferably 5wt% at the most again.
30. according to the method for any one of claim 14-29, wherein this granulation step e) after be pressing step f).
31. methods according to claim 30, wherein this pressing step f) be pill or tabletting.
The 32. functionalized natural or purposes of synthetic calcium carbonate in the at once floating gastric retention preparaton of any one of claim 1-13.
33. functionalized natural or synthetic calcium carbonates are for the preparation of the purposes in any one of claim 14-30 of floating gastric retention preparaton at once.
34. tablets comprising the at once floating gastric retention preparaton of any one of claim 1-13, micro tablet, granule, capsule or pill.
35. tablets comprising floating gastric retention preparaton at once, micro tablet, granule, capsule or pill, wherein this preparaton is obtained by the method for any one of claim 14-31.
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| EP12188419.1A EP2719376B1 (en) | 2012-10-12 | 2012-10-12 | Gastroretentive drug formulation and delivery systems and their method of preparation using functionalized calcium carbonate |
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| US201261713691P | 2012-10-15 | 2012-10-15 | |
| US61/713,691 | 2012-10-15 | ||
| PCT/EP2013/071140 WO2014057026A1 (en) | 2012-10-12 | 2013-10-10 | Gastroretentive drug formulation and delivery systems and their method of preparation using functionalized calcium carbonate |
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| CN104736145B CN104736145B (en) | 2017-06-23 |
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| CN201380052939.6A Active CN104736145B (en) | 2012-10-12 | 2013-10-10 | Gastric retention medicine preparaton and delivery system and its preparation method using functionalization calcium carbonate |
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| EP (2) | EP2719376B1 (en) |
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